Cocaine and methamphetamine (meth) abuse is an urgent public health problem. While addiction involves many factors, a better understanding of the biological changes after drug use would significantly advance the development of new therapeutic strategies. There is a recent increased interest in determining how circuits that interface with the mesolimbic reward system regulates psychostimulant addiction. One such circuit are Melanin Concentrating Hormone (MCH) neurons that originate from the lateral hypothalamus. While these glucose-sensing neurons are studied primarily in energy balance, sleep-wakefulness, alcohol and food intake, there are hints that these neurons also are involved in processes underlying cocaine and meth addiction-like behavior. Our current research into the role of MCH in addiction has been hampered by a lack of neuronal specificity, and has not used preclinical self-administration approaches that consistently produce addiction-like behaviors in rats. Moreover, it has been discovered that cocaine changes brain glucose levels at a behaviorally relevant timescale, but how cocaine can change the activity of MCH neurons or their input into the mesolimbic system remains unknown. This project seeks to determine the changes in MCH neuronal activity after psychostimulant experience and link it to extracellular glucose levels in vivo (Aim 1). Experiments will determine the functional role of LH MCH neurons in regulating long access and intermittent access cocaine or meth self-administration, two approaches that produce addiction-like behavior in rats (Aim 2). This project will use state of the art neuroscience tools including optical recording of genetically encoded calcium indicators, in vivo glucose monitoring using enzyme-linked biosensors, and genetically targeted designer receptors exclusively activated by designer drugs. Using these approaches will allow us to determine whether cocaine and meth experience alters the response to psychostimulant drugs via a glucose related mechanism, and if the activity of MCH neurons regulate addiction-like symptoms. This will result in technical development and critical preliminary data for subsequent applications. Future proposals will focus on how MCH neurons impact central stress areas, contributing to addiction and relapse and determining how MCH neurons and their specific projections contribute towards basic reward-related processes like incentive salience attribution normally regulated by the mesolimbic system. Understanding the biological mechanisms underlying addiction, is an important component to developing effective interventions that can be applied both at a national and local level.